Parkinson's disease is a degenerative disorder caused by the loss of dopaminergic neurons in the part of the brain that controls motor function. The disease is characterized by progressive motor dysfunction, cognitive disability, and death. Conventional treatments employ 3-hydroxy-L-tyrosine, commonly referred to as levodopa or L-DOPA. L-DOPA is a precursor in the natural production of dopamine, and it enhances levels of dopamine in the central nervous system. Unfortunately, L-DOPA loses its efficacy after prolonged use, presumably because of the continued degeneration of the neurons that convert it to dopamine. Prolonged treatment generally requires the use of additional dopaminergic agonists be used in combination with L-DOPA. Typical agents commonly utilized in adjunctive therapy with L-DOPA include pergolide and bromocryptine. Such agents often cause undesirable side-effects such as adverse cardiac effects, increased states of confusion and hallucinations, and exacerbation of pre-existing dyskinesia.
The need continues to find new agents that are useful to treat Parkinson's disease. Ideally, an agent
will replace the use of L-DOPA completely, and be sufficiently effective and safe such that adjunctive
therapy with additional drugs is obviated. We have now discovered a series of oxime and hydrazone derivatives of a naphthalenone which exhibit good in vivo agonist activity at both the D1 and the D2 dopamine receptors. The compounds are thus useful for treating Parkinson's disease.